The dangers of substance abuse in adolescents with
chronic kidney disease: a review of the literature.

Abstract:

Although there exist no specific data on the prevalence of
substance abuse among children and adolescents with chronic kidney
diseases (CKD), the magnitude of this problem should not be
underestimated, as almost half of twelfth-graders in the U.S. admit to a
history of using illegal drugs at least once when asked (National
Institute on Drug Abuse, 2011). According to the 2010 Canadian Alcohol
and Drug Use Monitoring Survey (Health Canada, n.d.), the prevalence of
drug abuse among Canadian youths and young adults aged 15 to 24 remains
higher than in adults older than 25 years of age, and the rates of drug
use (excluding cannabis) in the past years were 7.9% and 0.8%,
respectively, illustrating an almost 10 times higher rate in the younger
age group (Health Canada, n.d.). Drug abuse can lead to numerous medical
problems, including renal injury, and it is clearly a major public
health concern, especially in patients with subnormal kidney function
(Vupputuri et al., 2004). As most of the children and adolescents that
suffer from CKD have long-term and trustful relationships with the
nephrology team, we have the obligation and are in an excellent position
to address this particular health issue (Finkelstein & Finkelstein,
2000; Kimmel, 2002; Kimmel, Cohen, & Peterson, 2008). This review
summarizes the available data on the nephrotoxic effects of various
commonly abused drugs with special emphasis on the additional damage
that occurs in patients with pre-existing CKD. These data were obtained
from a thorough search of the available primary literature, specifically
using the PubMed database. The purpose is to provide health
professionals with a resource to properly educate their CKD patients on
the dangers of these drugs.

1. Recognize that substance abuse in adolescence is common, and
that adolescents suffering from chronic illness may be more predisposed
to substance abuse.

2. Discuss the nephrotoxic effects of various substances of abuse
in adolescents with chronic kidney disease (CKD).

3. Understand the role of the nephrology team in educating CKD
patients about the risks of substance abuse.

Neurodevelopment during the adolescence period involves growth and
remodelling of various areas of the brain that are associated with
impulsivity and addiction, thereby predisposing them to risk-taking
behaviours, including substance abuse (Chambers, Taylor, & Potenza,
2003; Crews, He, & Hodge, 2007). Health Canada has recently released
the results of the 2010 CADUMS, which demonstrated that among the young
individuals surveyed (aged 15 to 24), 41.4% reported lifetime use of
cannabis (Health Canada, n.d.). Even more worrisome is that among these
young drug users, 24.7% also reported harm to self in the past year.
Children and adolescents with CKD are constantly exposed to stresses,
which may further aggravate the situation. There are also studies in the
literature suggesting that adolescents with chronic illnesses are more
predisposed to smoking, drinking and drug addiction (Scaramuzza et al.,
2010; Suris & Parera, 2005). Specifically, according to a study from
the National Center on Addiction and Substance Abuse at Columbia
University, nine in 10 people who suffer from drug addiction begin to
smoke or drink and/or use other drugs before the age of 18 (The National
Center on Addiction and Substance Abuse at Columbia University, 2011).
The 2004 Canadian Addiction Survey analyzed the risks associated with
tobacco use among youth aged 15 to 19, and the results indicated that
tobacco use is a significant indicator for drug abuse (Davis, 2006).
Studies have also suggested that young individuals are more prone to
develop drug dependency and to suffer from the mental side effects, when
compared to adults. Therefore, the risk of smoking and drinking
behaviours among pediatric patients with chronic kidney diseases should
not be underestimated (Chen, O'Brien, & Anthony, 2005; DeWit,
Adlaf, Offord, & Ogborne, 2000; Raphael, Wooding, Stevens, &
Connor, 2005). Moreover, it is important to keep in mind that not all
adolescents will admit to drug use when asked by a health care provider.
It is imperative for the team to have a high index of suspicion and be
ready to provide education and guidance to adolescent patients about the
risks of substance abuse. Table 1 depicts the most commonly abused drugs
and their common physiologic side effects that are listed on the web
page of the National Institute on Drug Abuse (n.d.). Nephrotoxicities
related to drug abuse can vary according to individual situations. It
may be due to the direct or indirect toxic effects of the drugs on the
kidneys and may encompass a spectrum or combinations of vascular,
glomerular and interstitial damage (Milroy & Parai, 2011). Table 2
depicts some common mechanisms of nephrotoxicities secondary to various
drugs. The renal toxic effects of the commonly abused drugs are being
discussed below. Although most of the information available in the
literature originated from studies in adult patients, these experiences
should also be useful in the care of adolescents.

Cannabinoids: Marijuana and hashish

Marijuana

Marijuana has different names (grass, joint, bud, Mary Jane, pot,
weed and skunk) and health care providers should familiarize themselves
with the names that are being used on the streets. Patients may display
symptoms of euphoria, delayed reaction, poor coordination, deterioration
in learning and loss of memory. According to the most recent CADUMS, the
median age for the initiation of marijuana abuse among young adults was
15.7 years (Health Canada, n.d.). Despite the fact that marijuana has
been one of the most commonly abused drugs in history, only a few
reports of renal infarctions in patients with a history of heavy
marijuana use could be found in the literature, (Lambrecht, Malbrain,
Coremans, Verbist, & Verhaegen, 1995; Le Guen, Gestin, Plat, Quehe,
& Bressollette, 2011). The exact mechanism has not yet been
elucidated and no direct links of renal injury to its use have been
established (Crowe, Howse, Bell, & Henry, 2000).

On the other hand, as cannabinoids are metabolized by the
cytochrome P450 enzyme system of the liver, they may interfere with the
metabolism of cyclosporine and tacrolimus, thereby increasing the risk
of calcineurin inhibitor toxicities (Davison & Davison, 2011;
Yamaori, Okamoto, Yamamoto, & Watanabe, 2011). As the kidney is the
primary route of elimination, the risk of accumulation of the
metabolites of cannabinoids increases in patients with impairment of
glomerular filtration (Davison & Davison, 2011). Additionally,
Bohatyrewicz et al. reported a case of a 27-year-old kidney allograft
recipient who developed de novo membranous nephropathy after
transplantation (Bohatyrewicz, Urasinska, Rozanski, & Ciechanowski,
2007). Even though the patient denied any previous exposure to
nephrotoxic agents, his urine showed high levels of [DELTA]
9-tetrahydrocannabinol (THC) (Bohatyrewicz, et al., 2007). This case
suggests a possible association between marijuana abuse and membranous
nephropathy (Bohatyrewicz, et al., 2007). Moreover, a recent study from
Australia provides compelling evidence that adolescents who abuse
marijuana are at risk of continuing to abuse other illicit drugs later
in life (Swift et al., 2011).

Opioids: Heroin and opium Heroin

Heroin is an acetylation product of morphine and has been one of
the most commonly abused illicit drugs in the United States (Dettmeyer,
Preuss, Wollersen, & Madea, 2005; Jaffe & Kimmel, 2006). It may
be called white horse, China white or smack. It can be taken by
sniffing, inhalation or injection. Although the data on heroin use among
young adults are not available in the most recent CADUMS, it has also
been a maorly abused drug among Canadians in the past (Fischer et al.,
2005). Unlike marijuana, there is a wide spectrum of heroin-associated
renal injuries, including injury secondary to rhabdomyolysis,
glomerulonephropathies and interstitial nephritis (Sreepada Rao,
Nicastri, & Friedman, 1977).

Cocaine is less commonly used among Canadian drug addicts between
the ages of 15 to 24, as only 2.7% of those surveyed admitted to cocaine
use in the past year (Health Canada, n.d.). Although cocaine is well
known for its cardiovascular effects, cocaine abuse can also be harmful
to the kidneys, and both acute and chronic kidney injuries have been
associated with cocaine use in healthy individuals (Garg et al., 2011;
Gitman & Singhal, 2004; Jaffe & Kimmel, 2006; Nzerue,
Hewan-Lowe, & Riley, 2000). Like other commonly abused drugs, the
metabolites of cocaine also rely on the kidneys as their main route of
excretion and, thus, the risk of accumulation of these products is much
higher in CKD patients (Churchwell & Mueller, 2007; Nzerue et al.,
2000).

It is speculative that cocaine abuse is more likely to induce
injury in patients with underlying renal insufficiencies by hastening
the progression of renal disease. A recent study has also shown that
cocaine users developed end stage renal diseases and required dialysis
at younger ages than the group not using cocaine (Gitman & Singhal,
2004).

Amphetamines

Amphetamines have been implicated in different forms of renal
diseases (Citron et al., 1970; Halpern & Citron, 1971; Koff,
Widrich, & Robbins, 1973; White, 2002). Acute kidney injuries
secondary to rhabdomyolysis have been associated with intravenous use of
methamphetamines (Ginsberg, Hertzman, & Schmidt-Nowara, 1970;
Kendrick, Hull, & Knochel, 1977). Furthermore, necrotizing angiitis
has also been described in adult amphetamine abusers (Citron et al.,
1970). Initial presentations include constitutional symptoms such as
weight loss, fever and chronic fatigue, and then progress to severe
abdominal and joint pain, cutaneous rashes and ulcers (Citron et al.,
1970). Patients with renal involvement usually have hematuria,
proteinuria, rapid progression of hypertension and worsening of renal
function, with histological findings that are very similar to
polyarteritis nodosa (Halpern & Citron, 1971). Interstitial
nephritis has also been reported, and some of these patients recovered
with corticosteroid therapy (Foley, Kapatkin, Verani, & Weinman,
1984).

Ketamine is a commonly used anesthetic drug with amnesic effect. It
is structurally related to PCP and is also known as special K. Case
reports have linked ketamine use to the development of inflammatory
cystitis and acute renal injury (Chu et al., 2007; Selby et al., 2008;
Shahani, Streutker, Dickson, & Stewart, 2007).

Prescription drug abuse, including hydrocodone and benzodiazepines,
is one of the fastest growing addiction problems. According to the 2011
estimated world requirements of narcotic drugs, Canadians rank third for
top consumers of oxycodone, only after France and the United States, and
are the top users of hydromorphone (Estimated World Requirements of
Narcotic Drugs for 2011, October update). Although there are no
nephrotoxic effects reported in patients who abuse hydrocodone, there is
evidence that benzodiazepine overdose may lead to renal injuries
including rhabdomyolysis and interstitial nephritis in patients with
pre-existing chronic renal diseases (Hojgaard, Andersen, &
Moller-Petersen, 1988; Sadjadi, McLaughlin, & Shah, 1987).

Although alcohol is not an illegal drug in Canada, it is a commonly
consumed beverage in adolescents that has the potential for harmful
effects. Alcohol was used during the past 30 days in 52.3% of youth
surveyed in the 2010 CADUMS report (Health Canada, n.d.). Binge drinking
in the past month has also been reported in 22.3% of students in grades
7 to 12 according to the Ontario Student Drug Use and Health Survey
(OSDUHS) (Paglia-Boak, 2011). Long-term consumption of ethanol can have
many deleterious effects on kidney function. Chronic alcoholism has been
shown to cause acute tubular necrosis and dysfunction (De Marchi et al.,
1993; Presti, Carollo, & Caimi, 2007). An autopsy series on chronic
alcoholics demonstrated a high incidence of IgA deposition in the
kidneys, which suggested the possible association of chronic alcoholism
and IgA nephropathy (Cecchin & De Marchi, 1996). Furthermore, there
are cases of acute kidney injuries resulting from alcohol-induced
rhabdomyolysis (Haapanen, Pellinen, & Partanen, 1984). Lastly,
ethanol consumption has also been implicated in hypertension when
consumed in amounts greater than 80 g daily in men and greater than 40 g
daily in women (Vamvakas, Teschner, Bahner, & Heidland, 1998).
Electrolyte abnormalities such as salt and water retention, and renal
loss of calcium, phosphate and magnesium due to alcohol-induced
hypoparathyroidism have also been linked to chronic alcoholism
(Vamvakas, et al., 1998). Moreover, long-term alcohol consumption is
also associated with hyperuricemia and predisposition to gout (Vamvakas,
et al., 1998). Thus, alcohol consumption should be discouraged in
patients with pre-existing CKD, as they would be at higher risk for
these alcohol-related kidney injuries.

Ethylene glycol

The ingestion of antifreeze, or other forms of ethylene glycol
(EG), often results in acute renal failure. U.S. poison centre
statistics show that about 5,000 people are treated for EG poisoning in
the United States every year, with about 20 to 40 fatalities (Bronstein
et al., 2009). The mechanism has not been established, but is thought to
result from the production of a toxic metabolite. Although the
"aldehyde" metabolites of EG, glycolaldehyde, and glyoxalate
have been suggested as the metabolites responsible, recent studies have
shown definitively that the accumulation of calcium oxalate monohydrate
(COM) crystals in kidney tissue produce renal tubular necrosis that
leads to kidney failure (McMartin, 2009). The blockade of EG metabolism
with fomepizole (or ethanol) to prevent formation of glycolate and
oxalate is the mainstay of current therapy for early stages of EG
poisoning. However, there are significant numbers of patients who remain
undiagnosed, either because of delay in getting to a hospital or
difficulties in making the diagnosis (Jacobsen, 1999). In these cases,
EG metabolism will have occurred before diagnosis, thus leading to
serious morbidity, including COM-induced renal failure. The only current
treatment for EG-induced renal failure is hemodialysis/
hemodialfiltration.

Tobacco

Tobacco use is widespread, making it the greatest cause of
morbidity and mortality in the United States (Ehlers et al., 2006).
While tobacco is notorious for its damaging effects on the respiratory
and cardiovascular systems, there is also evidence for its harmful
effects on the kidneys. Firstly, tobacco use increases the risk for
kidney cancers such as renal cell carcinoma (Cooper, 2006). Furthermore,
nicotine, a component of tobacco, has been shown to worsen proteinuria
(Cooper, 2006). Smoking has been shown to increase the risk of
developing microalbuminuria in healthy individuals (Hillege et al.,
2001) and accelerate the progression of CKD in diabetic patients
(Cooper, 2006). A prospective study in hypertensive patients has also
suggested that smoking is one of the major risk factors of renal
function deterioration (Regalado, Yang, & Wesson, 2000). Among renal
allograft recipients, smoking has also been associated with higher rates
of graft loss (Kasiske & Klinger, 2000; Sung, Althoen, Howell, Ojo,
& Merion, 2001).

The role of nephrology nurses

As nephrology nurses have had long-term and trustful relationships
with the adolescents with CKD, they are, thus, in the best position to
help those who are struggling with substance abuse at different levels.
Hence, it is pivotal for nephrology nurses to keep abreast of their
knowledge regarding how to detect the signs and symptoms of drug abuse
and familiarize themselves with the relevant resources within their
community. As it is not the routine for the nephrology team to screen
their patients, it is imperative that we have a high index of suspicion,
especially in those at high risk for drug abuse, including those with a
co-existing psychiatric illness and a family history of substance abuse
(Leslie, 2008; Swadi, 1999). Signs may be subtle and easily missed, such
as non-adherence to a therapeutic regimen and mood instability. If in
doubt, the physicians need to be notified for further evaluations. There
are a number of validated clinical tools that can be used in adolescents
for assessment of substance abuse, including the Personal Experience
Screening Questionnaire (PESQ), Alcohol Use Disorders Identification
Test (AUDIT) and the CRAFFT Screening Test (Knight, Sherritt, Shrier,
Harris, & Chang, 2002; Saunders, Aasland, Babor, de la Fuente, &
Grant, 1993; Winters, 1992). The authors find their colleagues in the
Adolescence Medicine and Clinical Psychology Departments particularly
helpful in administering these tests. When intervention is necessary,
the nephrology team can work with the family to arrange counselling and
psychological support. It is not the intention of the authors to discuss
the community resources for youth suffering from drug abuse; rather, it
is recommended that readers refer to the National Anti-Drug Strategy
website of the Government of Canada for further information.

Conclusion

Adolescents are at a neurodevelopmental stage that renders them
more prone to addiction, and there is substantial evidence that such
behaviour has significant health consequences. The deleterious effects
of drug abuse on the kidney, especially in patients with pre-existing
renal insufficiencies, cannot be over emphasized. Since experimenting
with various drugs is common in the teenage years, it is crucial for
pediatric patients with CKD to recognize that they are particularly
vulnerable to the complications. It is the responsibility of the renal
team to be their advocates and provide advice and guidance. Nephrology
nurses are in a position to recognize and assist adolescents who suffer
from CKD and substance abuse by screening for related signs and
referring them to appropriate counselling services.

RELATED ARTICLE: The dangers of substance abuse in adolescents with
chronic kidney disease: a review of the literature

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